US4876276A - (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols - Google Patents

(3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols Download PDF

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Publication number
US4876276A
US4876276A US07/112,705 US11270587A US4876276A US 4876276 A US4876276 A US 4876276A US 11270587 A US11270587 A US 11270587A US 4876276 A US4876276 A US 4876276A
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group
carbon atoms
straight
patient
branched alkyl
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US07/112,705
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Raphael Mechoulam
Jeffery J. Feigenbaum
Naphtali Lander
Morris Srebnik
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Yissum Research Development Co of Hebrew University of Jerusalem
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Yissum Research Development Co of Hebrew University of Jerusalem
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Assigned to YISSUM RESEARCH DEVELOPMENT CO. OF THE HEBREW UNIVERSITY OF JERUSALEM reassignment YISSUM RESEARCH DEVELOPMENT CO. OF THE HEBREW UNIVERSITY OF JERUSALEM ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SREBNIK, MORRIS, LANDER, NAPHTALI, FEIGENBAUM, JEFFERY J., MECHOULAM, RAPHAEL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • the invention relates to pharmaceutical compositions which are potent analgetic, antiemetic and antiglaucoma agents, and which are essentially free of cannabimimetic effects.
  • the active ingredients of the novel pharmaceutical compositions are (3S,4S)-7-hyroxy- ⁇ 6 -tetrahydrocannabinol homologs and derivatives, essentially free of the (3R,4R)-form.
  • the compounds are novel per se and are part of the invention.
  • Cannabinoid compounds are known to have a wide variety of biological effect on mammals, many of which are of potential therapeutical value, see R Mechoulam Ed., Cannabinoids as Therapeutic Agents CRS Press, Boca Baton, Fla. 1986.
  • the drawback of many of the compounds which have such potential are side effects, and especially cannabimimetic effects which are highly undesirable.
  • the drawbacks have been overcome to a large extent, and the pharmaceutical compositions of the present invention are essentially devoid of such psychotropic side-effects.
  • R. Mechoulam et al in The Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects, Academic Press, Ed. S. Agurell, W. L. Dewey and R. S. Willette, Orlando, Fla., 1984, pp 777-795, there have been published data on compounds which have a chirality which is opposite to that of the natural compounds, i.e. it is (3S,4S) rather than (3R,4R) of the natural compounds.
  • An example of these compounds is the 1",2"-dimethyl heptyl homolog of (3S,4S)-(+)- ⁇ 6 -THC.
  • the present invention overcomes these drawbacks, and there is provided a synthetic route which makes possible to obtain the (3S,4S) enantiomers of the desired derivatives in essentially pure form, devoid of the undesired admixture of the (3R,4R) enantiomers.
  • the invention relates to compounds having the (3S,4S) configuration, and which are essentially free of the (3R,4R) enantiomer, which are of the formula: ##STR1## wherein R is selected from:
  • R' is straight or branched alkyl of 5 to 9 carbon atoms, or a straight or branched alkyl substituted at the terminal carbon atom by a phenyl group;
  • n is an integer of from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms;
  • compositions which contain as active ingredient an effective quantity of a compound of the formula ##STR2## as well as functional derivatives thereof, which have the (3S,4S) configuration and which are essentially devoid of content of an appreciable contamination by the (3R,4R) enantiomer.
  • the compositions of the invention are of value as analgetics, (in cases of either acute or chronic pain), antiemetics and as antiglaucoma agents. They are practically devoid of the undesired side-effects of the cannabimimetic type.
  • Preferred compounds of the above formula, for the intended uses are those wherein the alkyl group is as follows:
  • the present invention also relates to Compound V in crystalline form, which due to its crystallinity allows enantiometic purification, resulting in Compounds of type II, X and XI, which are the most potent compounds for use according to the invention, in pure enantiometic form.
  • the compounds of the invention are administered as pharmaceutical compositions containing certain cupric salts, or these are administered separately.
  • the effective dosages for humans are within the range of from 0.1 to about 100 mg per unit dosage form. They can be administered by injection, by oral route or by intracular topical application or in the form of suppositories. ##STR4##
  • a further salient feature of the above synthesis is the protection of the allylic alcohol in III by a bulky ester moiety. If a non-bulky ester is used i.e. an acetate, the ring closure to IIa (reaction f) does not take place as described. Instead, compound IX (reaction g) is obtained solely or predominantly.
  • Compound IIa (+form) shows no cannabimimetic activity when tested by the ring test (ref 3 ), rotarod test (ref 4), and by drug discrimination tests in rats and pigeons (ref 5).
  • compound (IIa) shows potent analgetic activity in the hot plate test for mice and rats, acetic acid writhing test in mice, the rat tail immersion test (see Table 1-3), in reduction of intraocular pressure in rabbits (Table 4) and in prevention of vomiting in pigeons (Table 5)
  • a The activity in some tests (in particular analgesia) lasts for several days. This is of considerable therapeutic importance, in particular when used against chronic pain; b: Best activity in all tests is obtained when the solution administered contains cupric salts in molar concentrations equal to (or up to 5 times higher than) the molar concentration of the active cannabinoid.
  • (+)-4-Hydroxy-myrtenyl pivalate (VI) (1.32 g, 5.24 mmol) in dry freshly distilled methylene chloride (50 ml) was added over a period of 30 min to a solution of 5-(1.1-dimethyl heptyl)resorcinol (1.24 g, 5.27 mmol) and dry anhydrous p-toluene sulfonic acid (270 mg) in dry methylene chloride (200 ml).
  • the solution was left at room temperature, under nitrogen for 60 min washed with a saturated solution of sodium bicarbonate, dried and evaporated.
  • the oil obtained was chromatographed on silica gel with 5% ether in petroleum ether as eluting solvent.
  • the first compound to be eluted was compound (IX) (30 mg) m.p. 154°-155°, ⁇ D-169° (ethanol); ⁇ (CDCl 3 ) 6.40 and 6.27 (aromatic H), 5.16 (m, C ⁇ CH 2 ), 3.79 (d, C-2H), 1.34, 1.21, 0.83 (methyl groups).
  • the second compound eluted is compound (VII), 60% yield a semi-solid, ⁇ D+75°; ⁇ max 1620 cm -1 ; ⁇ (CDCL 3 ) 6.21, 6.0, 4.61, 4.09, 1.39, 1.20, 1.18, 1.10, 0.82.
  • n can be 1 to 7.
  • the alkoxy group in this case was OCH 3 , OC 2 H 5 , OC 3 H 7 (n), OC 4 H 9 (n), OCH(CH 3 ) 2 , OCH(CH 3 )C 2 H 5 , OCH 2 CH(CH 3 ) 2 , etc.
  • a further group we used was based on 5 substituted resorcinols (type XIV) leading to cannabinoids of type XI.
  • the C-5 groups in this case were:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US07/112,705 1986-10-24 1987-10-26 (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols Expired - Lifetime US4876276A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL80411 1986-10-24
IL80411A IL80411A (en) 1986-10-24 1986-10-24 Preparation of dibenzopyranol derivatives and pharmaceutical compositions containing them

Publications (1)

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US4876276A true US4876276A (en) 1989-10-24

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US (1) US4876276A (fr)
CA (1) CA1286682C (fr)
DE (1) DE3735990C2 (fr)
FR (1) FR2623809B1 (fr)
GB (1) GB2196964B (fr)
IL (1) IL80411A (fr)

Cited By (70)

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AU631262B2 (en) * 1989-11-07 1992-11-19 Ramot University Authority For Applied Research And Industrial Development Ltd. Nmda-blocking pharmaceutical compositions
US5180736A (en) * 1989-03-23 1993-01-19 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents
US5284867A (en) * 1989-11-07 1994-02-08 Yissum Research Development Company Of The Hebrew University In Jerusalem NMDA-blocking pharmaceutical compositions
US5352683A (en) * 1993-03-05 1994-10-04 Virginia Commonwealth University Medical College Of Virginia Method for the treatment of chronic pain
WO1995020958A1 (fr) * 1994-02-07 1995-08-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Derives de dexanabinol et leur emploi en tant que compositions pharmaceutiques neuroprotectrices
US5538993A (en) * 1991-09-12 1996-07-23 Yissum Research Development Company Certain tetrahydrocannabinol-7-oic acid derivatives
US5635530A (en) * 1991-09-12 1997-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and derivatives thereof, processors for their preparation and pharmaceutical compositions containing them
US5847128A (en) * 1998-05-29 1998-12-08 Virginia Commonwealth University Water soluble derivatives of cannabinoids
WO1999020268A1 (fr) * 1997-10-17 1999-04-29 Atlantic Pharmaceuticals, Inc. Acides (3r, 4r) - δ8 - tetrahydrocannabinol - 11 - oique s'utilisant comme agents anti-inflammatoires et analgesiques
US6096740A (en) * 1990-11-06 2000-08-01 Ramot University Authority For Applied Research And Industrial Development Ltd. Dexanabinol derivatives and their use as neuroprotective pharmaceutical compositions
US6132762A (en) * 1997-05-05 2000-10-17 Cristobal; Walter Transcutaneous application of marijuana
EP0876143A4 (fr) * 1995-09-11 2001-06-27 Yissum Res Dev Co Produits pharmaceutiques inhibiteurs du facteur de necrose tumorale alpha (tnf-alpha)
US6274635B1 (en) 1999-03-22 2001-08-14 Immugen Pharmaceuticals Inc. Alkylated resorcinol derivatives for the treatment of immune diseases
WO2001028497A3 (fr) * 1999-10-18 2001-09-13 Univ Connecticut Nouveaux agonistes de cannabinoides bicycliques destines au recepteur de cannabinoides
US6566560B2 (en) 1999-03-22 2003-05-20 Immugen Pharmaceuticals, Inc. Resorcinolic compounds
US20030120094A1 (en) * 1998-05-04 2003-06-26 Alexandros Makriyannis Novel analgesic and immunomodulatory cannabinoids
US20030149082A1 (en) * 1998-06-09 2003-08-07 Alexandros Makriyannis Inhibitors of the anandamide transporter as analgesic agents
US6630507B1 (en) 1998-04-21 2003-10-07 The United States Of America As Represented By The Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US6649658B1 (en) * 1999-04-16 2003-11-18 Euphar Group Srl (−)-Verbenone derivatives
US20030232101A1 (en) * 2002-03-18 2003-12-18 Immugen Pharmaceuticals, Inc. Topical formulations of resorcinols and cannibinoids and methods of use
US20040077649A1 (en) * 2001-01-26 2004-04-22 Alexandros Makriyannis Novel cannabimimetic ligands
US20040082543A1 (en) * 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
GB2394894A (en) * 2002-11-04 2004-05-12 G W Pharma Ltd New use for pharmaceutical composition
US20040138315A1 (en) * 2000-09-28 2004-07-15 Immugen Pharmaceuticals, Inc. Methods and compounds for inhibiting eicosanoid metabolism and platelet aggregation
US20040192667A1 (en) * 2001-08-31 2004-09-30 University Of Connecticut Novel pyrazole analogs acting on cannabinoid receptors
US20040236101A1 (en) * 2001-10-26 2004-11-25 Alexandros Makriyannis Heteroindanes a new class of potent cannabimimetic ligands
US20040236116A1 (en) * 2001-07-13 2004-11-25 Alexandros Makriyannis Novel bicyclic and tricyclic cannabinoids
US20040242870A1 (en) * 2000-09-28 2004-12-02 Immugen Pharmaceuticals, Inc. Antiviral methods and compounds
US20050020679A1 (en) * 1998-06-09 2005-01-27 University Of Connecticut Inhibitors of the anandamide transporter
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
US20050137173A1 (en) * 1999-10-18 2005-06-23 Alexandros Makriyannis Bicyclic cannabinoid agonists for the cannabinoid receptor
US20050192341A1 (en) * 2002-09-05 2005-09-01 Seth Kindler Non-psychotropic cannabinoids for prevention of cognitive impairment
US20050266061A1 (en) * 2000-12-22 2005-12-01 Stinchcomb Audra L Transdermal delivery of cannabinoids
US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
US20060030563A1 (en) * 1999-10-18 2006-02-09 Alexandros Makriyannis Novel pyrazole analogs acting on cannabinoid receptors
US20060100208A1 (en) * 1999-10-18 2006-05-11 Alexandros Makriyannis Pyrazole derivatives as cannabinoid receptor antagonists
US20060128738A1 (en) * 2004-12-13 2006-06-15 Indevus Pharmaceuticals, Inc. Treatment of interstitial cystitis using cannabinoid analogs
US20060128794A1 (en) * 2004-12-13 2006-06-15 Indevus Pharmaceuticals, Inc. Treatment of interstitial cystitis using (6aR,10aR)-delta8-tetrahydrocannabinol-11-OIC acids
US20060189610A1 (en) * 1999-10-18 2006-08-24 Alexandros Makriyannis Peripheral cannabinoid receptor (CB2) selective ligands
USRE39300E1 (en) 1993-01-28 2006-09-19 Virginia Commonwealth University Medical College Of Virginia Inhibiting the development of tolerance to and/or dependence on an addictive substance
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
US7173027B2 (en) 2001-01-29 2007-02-06 University Of Connecticut Receptor selective cannabimimetic aminoalkylindoles
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
US20070060636A1 (en) * 2002-12-04 2007-03-15 Haim Aviv High enantiomeric purity dexanabinol for pharmaceutical compositions
US20070093665A1 (en) * 2005-09-29 2007-04-26 Amr Technology, Inc. Process for production of delta-9- tetrahydrocannabinol
US7276613B1 (en) 1998-11-24 2007-10-02 University Of Connecticut Retro-anandamides, high affinity and stability cannabinoid receptor ligands
US20090036523A1 (en) * 2007-07-30 2009-02-05 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
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US20090247619A1 (en) * 2008-03-06 2009-10-01 University Of Kentucky Cannabinoid-Containing Compositions and Methods for Their Use
US20110033376A1 (en) * 2007-07-06 2011-02-10 Malcolm Philip Young Treatment of Melanoma
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WO2013160645A1 (fr) 2012-04-26 2013-10-31 E-Therapeutics Plc Dexanabinol ou un dérivé de celui-ci destiné à être utilisé dans le traitement du cancer dans des plages de doses de 2 à 30 mg/kg
WO2016014454A1 (fr) 2014-07-21 2016-01-28 Pharmaceutical Productions, Inc. Composition de forme galénique solide pour une administration par voie buccale ou sublinguale de cannabinoïdes
US9585867B2 (en) 2015-08-06 2017-03-07 Charles Everett Ankner Cannabinod formulation for the sedation of a human or animal
WO2017068349A1 (fr) 2015-10-23 2017-04-27 E-Therapeutics Plc Cannabinoïde pour utilisation en immunothérapie
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WO2019106652A1 (fr) 2017-11-29 2019-06-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Compositions de cannabinoïdes et méthodes
WO2020014200A1 (fr) 2018-07-09 2020-01-16 Volker Berl Formulations stabilisées de compositions cannabinoïdes
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WO2021019536A1 (fr) 2019-07-30 2021-02-04 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Méthodes de régulation de la synthèse de cannabinoïdes chez la plante ou dans des cellules et plantes et cellules ainsi produites
EP4124336A1 (fr) 2021-07-30 2023-02-01 Cannamedical Pharma GmbH Timbre transmucosal comprenant un cannabinoïde et/ou un opioïde
US12029719B2 (en) 2021-04-16 2024-07-09 Allen Morgan Compounds comprising cannabinoids and other natural ingredients for alieving premenstrual, menstrual and menopausal symptoms
US12029718B2 (en) 2021-11-09 2024-07-09 Cct Sciences, Llc Process for production of essentially pure delta-9-tetrahydrocannabinol
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Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5180736A (en) * 1989-03-23 1993-01-19 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents
AU631262B2 (en) * 1989-11-07 1992-11-19 Ramot University Authority For Applied Research And Industrial Development Ltd. Nmda-blocking pharmaceutical compositions
US5284867A (en) * 1989-11-07 1994-02-08 Yissum Research Development Company Of The Hebrew University In Jerusalem NMDA-blocking pharmaceutical compositions
EP0427518B1 (fr) * 1989-11-07 1995-03-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composés de NMDA-blocage, compositions pharmaceutiques, leur préparation et leur usage
JPH0768235B2 (ja) 1989-11-07 1995-07-26 イースム、リサーチ、デベロプメント、カンパニー、オブ、ザ、ヘブライ、ユニバーシティー、オブ、イエルサレム Ｎｍｄａ遮断薬剤組成物
US5521215A (en) * 1989-11-07 1996-05-28 Ramot University Authority For Applied Research And Industrial Development Ltd. NMDA-blocking pharmaceuticals
US6096740A (en) * 1990-11-06 2000-08-01 Ramot University Authority For Applied Research And Industrial Development Ltd. Dexanabinol derivatives and their use as neuroprotective pharmaceutical compositions
US5538993A (en) * 1991-09-12 1996-07-23 Yissum Research Development Company Certain tetrahydrocannabinol-7-oic acid derivatives
US5635530A (en) * 1991-09-12 1997-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and derivatives thereof, processors for their preparation and pharmaceutical compositions containing them
USRE39300E1 (en) 1993-01-28 2006-09-19 Virginia Commonwealth University Medical College Of Virginia Inhibiting the development of tolerance to and/or dependence on an addictive substance
US5352683A (en) * 1993-03-05 1994-10-04 Virginia Commonwealth University Medical College Of Virginia Method for the treatment of chronic pain
AU690221B2 (en) * 1994-02-07 1998-04-23 Pharmos Corporation Dexanabinol derivatives and their use as neuroprotective pharmaceutical compositions
WO1995020958A1 (fr) * 1994-02-07 1995-08-10 Ramot University Authority For Applied Research And Industrial Development Ltd. Derives de dexanabinol et leur emploi en tant que compositions pharmaceutiques neuroprotectrices
EP0876143A4 (fr) * 1995-09-11 2001-06-27 Yissum Res Dev Co Produits pharmaceutiques inhibiteurs du facteur de necrose tumorale alpha (tnf-alpha)
US6132762A (en) * 1997-05-05 2000-10-17 Cristobal; Walter Transcutaneous application of marijuana
US6162829A (en) * 1997-10-17 2000-12-19 Atlantic Pharmaceuticals, Inc. (3R,4R)-Δ8 -tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
US6355650B1 (en) 1997-10-17 2002-03-12 Atlantic Technology Ventures, Inc. (3R,4R)-Δ8-tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
WO1999020268A1 (fr) * 1997-10-17 1999-04-29 Atlantic Pharmaceuticals, Inc. Acides (3r, 4r) - δ8 - tetrahydrocannabinol - 11 - oique s'utilisant comme agents anti-inflammatoires et analgesiques
US6630507B1 (en) 1998-04-21 2003-10-07 The United States Of America As Represented By The Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
US20050239874A1 (en) * 1998-05-04 2005-10-27 University Of Connecticut Novel analgesic and immunomodulatory cannabinoids
US20030120094A1 (en) * 1998-05-04 2003-06-26 Alexandros Makriyannis Novel analgesic and immunomodulatory cannabinoids
US5847128A (en) * 1998-05-29 1998-12-08 Virginia Commonwealth University Water soluble derivatives of cannabinoids
US20030149082A1 (en) * 1998-06-09 2003-08-07 Alexandros Makriyannis Inhibitors of the anandamide transporter as analgesic agents
US7589220B2 (en) 1998-06-09 2009-09-15 University Of Connecticut Inhibitors of the anandamide transporter
US7897598B2 (en) 1998-06-09 2011-03-01 Alexandros Makriyannis Inhibitors of the anandamide transporter
US20050020679A1 (en) * 1998-06-09 2005-01-27 University Of Connecticut Inhibitors of the anandamide transporter
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
US7276613B1 (en) 1998-11-24 2007-10-02 University Of Connecticut Retro-anandamides, high affinity and stability cannabinoid receptor ligands
US6566560B2 (en) 1999-03-22 2003-05-20 Immugen Pharmaceuticals, Inc. Resorcinolic compounds
US7105685B2 (en) 1999-03-22 2006-09-12 Travis Craig R Cannabinol derivatives
US6274635B1 (en) 1999-03-22 2001-08-14 Immugen Pharmaceuticals Inc. Alkylated resorcinol derivatives for the treatment of immune diseases
US6649658B1 (en) * 1999-04-16 2003-11-18 Euphar Group Srl (−)-Verbenone derivatives
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FR2623809A1 (fr) 1989-06-02
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IL80411A0 (en) 1987-01-30
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DE3735990C2 (de) 1998-10-08
GB2196964A (en) 1988-05-11
FR2623809B1 (fr) 1994-02-11
DE3735990A1 (de) 1988-04-28
IL80411A (en) 1991-08-16

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